ABSTRACT
Persistently activated JAK/STAT3 signaling pathway plays a pivotal role in various human cancers including major carcinomas and hematologic tumors, and is implicated in cancer cell survival and proliferation. Therefore, inhibition of JAK/STAT3 signaling may be a clinical application in cancer therapy. Here, we report that 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo [1,3]oxathiol-4-one (BOT-4-one), a small molecule inhibitor of JAK/STAT3 signaling, induces apoptosis through inhibition of STAT3 activation. BOT-4-one suppressed cytokine (upd)-induced tyrosine phosphorylation and transcriptional activity of STAT92E, the sole Drosophila STAT homolog. Consequently, BOT-4-one significantly inhibited STAT3 tyrosine phosphorylation and expression of STAT3 downstream target gene SOCS3 in various human cancer cell lines, and its effect was more potent in JAK3-activated Hodgkin's lymphoma cell line than in JAK2-activated breast cancer and prostate cancer cell lines. In addition, BOT-4-one-treated Hodgkin's lymphoma cells showed decreased cell survival and proliferation by inducing apoptosis through down-regulation of STAT3 downstream target anti-apoptotic gene expression. These results suggest that BOT-4-one is a novel small molecule inhibitor of JAK3/STAT3 signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK3/STAT3 signaling, specifically Hodgkin's lymphoma.
Subject(s)
Animals , Humans , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Drosophila/enzymology , Drosophila Proteins/antagonists & inhibitors , Enzyme Activation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Janus Kinase 3/antagonists & inhibitors , Lymphoma/enzymology , Phosphorylation/drug effects , STAT Transcription Factors/antagonists & inhibitors , STAT3 Transcription Factor/antagonists & inhibitors , Signal Transduction/drug effectsABSTRACT
We present evidence for coexistence of three different Drosophila species by rescheduling their life history traits in a natural population using the same resource, at the same time and same place. D. ananassae has faster larval development time (DT) and faster DT(egg-fly) than other two species thus utilizing the resources at maximum at both larval and adult stages respectively. Therefore, D. ananassae skips the interspecific competition at pre-adult stage but suffers more from intraspecific competition. However, D. melanogaster and D. biarmipes have rescheduled their various life history traits to avoid interspecific competition. Differences of ranks tests for various life history traits suggest that except for DT(egg-pupa), the difference of ranks is highest for the combination of D. melanogaster and D. ananassae for all other life history traits. This difference is maintained by tradeoffs between larval development time and pupal period and between pupal period and DT(egg-pupa) in D. ananassae.
Subject(s)
Animals , Body Size/genetics , Drosophila/enzymology , Female , Larva/enzymology , Life Cycle Stages/physiology , Male , Reproduction/physiology , Species Specificity , TemperatureABSTRACT
We have isolated and purified two parental homodimers and a unique heterodimer of acid phosphatase [coded by Acph-1 (1.05)(F) and Acph-1 (0.95)(S)] from isogenic homozygotes and heterozygotes of Drosophila malerkotliana. F and S produce qualitatively different allozymes and the two alleles are expressed equally within and across all three genotypes and F and S play an equal role in the epigenetics of dominance. Subunit interaction in the heterodimer over a wide range of H+ concentrations accounts for the epigenetics of dominance for enzyme activity.